Pharmacological and Genetic Approaches to Downregulate FIS1 Mitigate Neuropathic Pain

作者：Chang-Lei Zhu, Shu‐Jiao Li, Zhipeng Lin, Zi-Wei Ni, Ke Tian, Yu-Lu Xia, Jing-Jing Tie, Xue-Yin Pu, Yun-Qiang Huang, Feifei Wu, Hui Liu, Kun-Long Zhang, Shuai Zhang, Yousheng Wu, Fei Tian, Nannan Liu, Cailian Ruan, Yanling Yang, Yayun Wang · 发表于：Journal of Neuroscience · 年份：2025 · DOI：10.1523/jneurosci.0523-25.2025 · 被引用次数：2 · 研究领域：Pain Mechanisms and Treatments、Neuropeptides and Animal Physiology、Hereditary Neurological Disorders

Despite the established link between neuropathic pain and abnormal mitochondrial fission in neurons, the specific role of mitochondrial fission protein 1 (FIS1) in this process remains to be fully elucidated. In this study, the subjects we investigated were 6-8-week-old male mice. Comprehensive behavioral tests and immunostaining, along with Western blot analysis, revealed that neuropathic pain induced by spared nerve injury (SNI) upregulated FIS1 expression in the spinal cord dorsal horn (SC-DH). Furthermore, artificially upregulated FIS1 in SC-DH caused hyperalgesia behaviors in normal mice, while downregulation alleviated neuropathic pain. Using GAD2-MITO and vGluT2-MITO transgenic mice, we found that mitochondria network of both excitatory and inhibitory neurons in the SC-DH were disrupted. Selective downregulation of FIS1 in excitatory neurons via vGluT2-Cre mice reversed mitochondrial impairments and alleviated neuropathic pain. Network pharmacological prediction analysis combined with pharmacological tests indicated that compounds capable of downregulating FIS1 expression, such as epigallocatechin gallate, the primary bioactive component of tea polyphenols, may possess analgesic properties. In contrast, cinnamic acid, an organic acid derived from cinnamon bark, did not exhibit the capability to downregulate FIS1 expression and consequently lacked analgesic efficacy. Our research findings suggest that FIS1 may represent a novel molecular target for the treatment of neur...